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Interventions for preventing the progression of autosomal dominant polycystic kidney disease.
Cochrane Database Syst Rev 2015; (7):CD010294CD

Abstract

BACKGROUND

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder causing kidney disease. Current clinical management of ADPKD focuses primarily on symptom control and reducing associated complications, particularly hypertension. In recent years, improved understanding of molecular and cellular mechanisms involved in kidney cyst growth and disease progression has resulted in new pharmaceutical agents to target disease pathogenesis to prevent progressive disease.

OBJECTIVES

We aimed to evaluate the effects of interventions for preventing ADPKD progression on kidney function, kidney endpoints, kidney structure, patient-centred endpoints (such as cardiovascular events, sudden death, all-cause mortality, hospitalisations, BP control, quality of life, and kidney pain), as well as the general and specific adverse effects related to their use.

SEARCH METHODS

We searched the Cochrane Renal Group's Specialised Register to 6 June 2015 using relevant search terms.

SELECTION CRITERIA

Randomised controlled trials (RCTs) comparing any interventions for preventing the progression of ADPKD with other interventions or placebo were considered for inclusion without language restriction.

DATA COLLECTION AND ANALYSIS

Two authors independently assessed study risks of bias and extracted data. We summarised treatment effects on clinical outcomes, kidney function and structure and adverse events using random effects meta-analysis. We assessed heterogeneity in estimated treatment effects using the Cochran Q test and I(2) statistic. Summary treatment estimates were calculated as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes and a risk ratio (RR) for dichotomous outcomes together with their 95% confidence intervals.

MAIN RESULTS

We included 30 studies (2039 participants) that investigated 11 pharmacological interventions (angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers, beta blockers, vasopressin receptor 2 (V2R) antagonists, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentaenoic acids, statins and vitamin D compounds) in this review.ACEi significantly reduced diastolic blood pressure (9 studies, 278 participants: MD -4.96 mm Hg, 95% CI -8.88 to -1.04), but had uncertain effects on kidney volumes (MD -42.50 mL, 95% CI -115.68 to 30.67), GFR (MD -3.41 mL/min/1.73 m(2), 95% CI -15.83 to 9.01), and SCr (MD -0.02 mg/dL, 95% CI -0.14 to 0.09), in data largely restricted to children. ACEi did not show different effects on GFR (MD -8.19 mL/min/1.73 m(2), 95% CI -29.46 to 13.07) and albuminuria (SMD -0.19, 95% CI -1.77 to 1.39) when compared with beta-blockers, or SCr (MD 0.00 mg/dL, 95% CI -0.09 to 0.10) when compared with ARBs.Data for effects of V2R antagonists on kidney function and volumes compared to placebo were limited to narrative information within a single study while these agents increased thirst (1444 participants: RR 2.70, 95% CI 2.24 to 3.24) and dry mouth (1455 participants: RR 1.33, 95% CI 1.01 to 1.76).Compared with no treatment, mTOR inhibitors had uncertain effects on kidney function (2 studies, 115 participants: MD 4.45 mL/min/1.73 m(2), 95% CI -3.20 to 12.11) and kidney volume (MD -0.08 L, 95% CI -0.75 to 0.59) but in three studies (560 participants) caused angioedema (RR 13.39, 95% CI 2.56 to 70.00), oral ulceration (RR 6.77, 95% CI 4.42 to 10.38), infections (RR 1.14, 95% CI 1.04 to 1.25) and diarrhoea (RR 1.70, 95% CI 1.26 to 2.29).Somatostatin analogues (6 studies, 138 participants) slightly improved SCr (MD -0.43 mg/dL, 95% CI -0.86 to -0.01) and total kidney volume (MD -0.62 L, 95% CI -1.22 to -0.01) but had no definite effects on GFR (MD 9.50 mL/min, 95% CI -4.45 to 23.44) and caused diarrhoea (RR 3.72, 95% CI 1.43 to 9.68).Data for calcium channel blockers, eicosapentaenoic acids, statins, vitamin D compounds and antiplatelet agents were sparse and inconclusive.Random sequence generation was adequate in eight studies, and in almost half of the studies, blinding was not present or not specified. Most studies did not adequately report outcomes, which adversely affected our ability to assess this bias. The overall drop-out rate was over 10% in nine studies, and few were conducted using intention-to-treat analyses.

AUTHORS' CONCLUSIONS

Although several interventions are available for patients with ADPKD, at present there is little or no evidence that treatment improves patient outcomes in this population and is associated with frequent adverse effects. Additional large randomised studies focused on patient-centred outcomes are needed.

Authors+Show Affiliations

Institute of Clinical Physiology, CNR - Italian National Council of Research, CNR-IFC Via Vallone Petrara c/o Ospedali Riuniti, Reggio Calabria, Italy, 89100.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Review
Systematic Review

Language

eng

PubMed ID

26171904

Citation

Bolignano, Davide, et al. "Interventions for Preventing the Progression of Autosomal Dominant Polycystic Kidney Disease." The Cochrane Database of Systematic Reviews, 2015, p. CD010294.
Bolignano D, Palmer SC, Ruospo M, et al. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2015.
Bolignano, D., Palmer, S. C., Ruospo, M., Zoccali, C., Craig, J. C., & Strippoli, G. F. (2015). Interventions for preventing the progression of autosomal dominant polycystic kidney disease. The Cochrane Database of Systematic Reviews, (7), p. CD010294. doi:10.1002/14651858.CD010294.pub2.
Bolignano D, et al. Interventions for Preventing the Progression of Autosomal Dominant Polycystic Kidney Disease. Cochrane Database Syst Rev. 2015 Jul 14;(7)CD010294. PubMed PMID: 26171904.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interventions for preventing the progression of autosomal dominant polycystic kidney disease. AU - Bolignano,Davide, AU - Palmer,Suetonia C, AU - Ruospo,Marinella, AU - Zoccali,Carmine, AU - Craig,Jonathan C, AU - Strippoli,Giovanni F M, Y1 - 2015/07/14/ PY - 2015/7/15/entrez PY - 2015/7/15/pubmed PY - 2016/2/10/medline SP - CD010294 EP - CD010294 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev IS - 7 N2 - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder causing kidney disease. Current clinical management of ADPKD focuses primarily on symptom control and reducing associated complications, particularly hypertension. In recent years, improved understanding of molecular and cellular mechanisms involved in kidney cyst growth and disease progression has resulted in new pharmaceutical agents to target disease pathogenesis to prevent progressive disease. OBJECTIVES: We aimed to evaluate the effects of interventions for preventing ADPKD progression on kidney function, kidney endpoints, kidney structure, patient-centred endpoints (such as cardiovascular events, sudden death, all-cause mortality, hospitalisations, BP control, quality of life, and kidney pain), as well as the general and specific adverse effects related to their use. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 6 June 2015 using relevant search terms. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any interventions for preventing the progression of ADPKD with other interventions or placebo were considered for inclusion without language restriction. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risks of bias and extracted data. We summarised treatment effects on clinical outcomes, kidney function and structure and adverse events using random effects meta-analysis. We assessed heterogeneity in estimated treatment effects using the Cochran Q test and I(2) statistic. Summary treatment estimates were calculated as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes and a risk ratio (RR) for dichotomous outcomes together with their 95% confidence intervals. MAIN RESULTS: We included 30 studies (2039 participants) that investigated 11 pharmacological interventions (angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers, beta blockers, vasopressin receptor 2 (V2R) antagonists, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentaenoic acids, statins and vitamin D compounds) in this review.ACEi significantly reduced diastolic blood pressure (9 studies, 278 participants: MD -4.96 mm Hg, 95% CI -8.88 to -1.04), but had uncertain effects on kidney volumes (MD -42.50 mL, 95% CI -115.68 to 30.67), GFR (MD -3.41 mL/min/1.73 m(2), 95% CI -15.83 to 9.01), and SCr (MD -0.02 mg/dL, 95% CI -0.14 to 0.09), in data largely restricted to children. ACEi did not show different effects on GFR (MD -8.19 mL/min/1.73 m(2), 95% CI -29.46 to 13.07) and albuminuria (SMD -0.19, 95% CI -1.77 to 1.39) when compared with beta-blockers, or SCr (MD 0.00 mg/dL, 95% CI -0.09 to 0.10) when compared with ARBs.Data for effects of V2R antagonists on kidney function and volumes compared to placebo were limited to narrative information within a single study while these agents increased thirst (1444 participants: RR 2.70, 95% CI 2.24 to 3.24) and dry mouth (1455 participants: RR 1.33, 95% CI 1.01 to 1.76).Compared with no treatment, mTOR inhibitors had uncertain effects on kidney function (2 studies, 115 participants: MD 4.45 mL/min/1.73 m(2), 95% CI -3.20 to 12.11) and kidney volume (MD -0.08 L, 95% CI -0.75 to 0.59) but in three studies (560 participants) caused angioedema (RR 13.39, 95% CI 2.56 to 70.00), oral ulceration (RR 6.77, 95% CI 4.42 to 10.38), infections (RR 1.14, 95% CI 1.04 to 1.25) and diarrhoea (RR 1.70, 95% CI 1.26 to 2.29).Somatostatin analogues (6 studies, 138 participants) slightly improved SCr (MD -0.43 mg/dL, 95% CI -0.86 to -0.01) and total kidney volume (MD -0.62 L, 95% CI -1.22 to -0.01) but had no definite effects on GFR (MD 9.50 mL/min, 95% CI -4.45 to 23.44) and caused diarrhoea (RR 3.72, 95% CI 1.43 to 9.68).Data for calcium channel blockers, eicosapentaenoic acids, statins, vitamin D compounds and antiplatelet agents were sparse and inconclusive.Random sequence generation was adequate in eight studies, and in almost half of the studies, blinding was not present or not specified. Most studies did not adequately report outcomes, which adversely affected our ability to assess this bias. The overall drop-out rate was over 10% in nine studies, and few were conducted using intention-to-treat analyses. AUTHORS' CONCLUSIONS: Although several interventions are available for patients with ADPKD, at present there is little or no evidence that treatment improves patient outcomes in this population and is associated with frequent adverse effects. Additional large randomised studies focused on patient-centred outcomes are needed. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/26171904/Interventions_for_preventing_the_progression_of_autosomal_dominant_polycystic_kidney_disease_ L2 - https://doi.org/10.1002/14651858.CD010294.pub2 DB - PRIME DP - Unbound Medicine ER -